Although big band swing faded from popularity as World War II ended, Kyser had to continue performing due to contractual obligations, and continued to log a few hits with Douglas, including two notable hits, "Ole [or Old] Buttermilk Sky" in 1946 and "The Old Lamp-Lighter" the following year. Kyser was responsible for giving him his show Business name, and he continued to perform with the band until Kyser retired in 1951 due to health problems. In 1950, he provided the singing voice of Prince Charming in Walt Disney's Cinderella.

In the 1950s, Douglas, living in Burbank, California, tried to keep his singing career going, working as house singer for a nightclub and going on the road to stay busy. By the middle of the decade, rock-and-roll and doo wop had taken over the charts, which left many older performers in the musical dustbin. In the leanest years, Douglas and his wife survived by successfully "flipping" their Los Angeles homes.

Douglas next surfaced in 1961 in Cleveland, where a onetime Chicago colleague hired him for $400 a week as an afternoon television talk-show host at WKYC-TV, then known as KYW-TV. The Mike Douglas Show rapidly gained popularity, and ultimately, national syndication in August 1963 on the five Westinghouse-owned stations. The show was broadcast live on KYW-TV in its city of origination, but this practice ended in 1965 after guest Zsa Zsa Gabor used the phrase "son of a bitch" when referring to stand-up Comedian and comic actor Morey Amsterdam of the Dick Van Dyke Show.

As KYW-TV's owner, Westinghouse Broadcasting, successfully had a station swap with NBC overturned by the FCC, Westinghouse returned to Philadelphia on June 19, 1965 with call letters KYW, along with the station swap came The Mike Douglas Show, which aired its first Philadelphia-based show on August 30, 1965. Even after ownership reverted to NBC, WKYC in Cleveland continued to carry the program for many years afterward. Guests ranged from Truman Capote and Richard Nixon to The Rolling Stones, Herman's Hermits and Kiss, with an occasional on-camera appearance by Tim Conway (who would later be discovered at WJW-TV, also in Cleveland). Moe Howard of "Three Stooges" fame was a guest several times, with a pie-fight inevitably happening at the end of the interview, and platform speaker on nonverbal communication (body language) Dr. Cody Sweet.

The show helped introduce entertainers such as Barbra Streisand and Aretha Franklin. After the move to Philadelphia, Douglas also attempted to revive his own singing career, logging his lone Top 40 single as a solo Artist, "The Men In My Little Girl's Life" in 1966. By 1967, The Mike Douglas Show was broadcast to 171 markets and 6,000,000 viewers each day, mostly women at home. It earned $10.5 million annually from advertisers, while its host was paid more than $500,000. In 1967, the program received the first Emmy Award for Individual Achievement in Daytime Television from the National Academy of Television Arts & Sciences.

Douglas sang "The Star-Spangled Banner" before the first Philadelphia Phillies game at Veterans Stadium on April 10, 1971, and also sang the national anthem prior to a Cincinnati Bengals-Miami Dolphins playoff game on December 23, 1973. He wrote two memoirs: My Story (1979) and I'll Be Right Back: Memories of TV's Greatest Talk Show (1999). He also wrote a cookbook, The Mike Douglas Cookbook (1969), featuring recipes from him, his family, and the show's guests. 40 years after Douglas began his talk show at KYW-TV, his granddaughter Debbie Voinovich Donley designed successor WKYC's new broadcast facility on Lakeside Avenue, completed in 2002. In 2007, a new documentary film Mike Douglas: Moments and Memories was shown on PBS stations. The Lily Tomlin comedy The Incredible Shrinking Woman shows the dwindling Pat Kramer appearing on Douglas's show, where he sings "Little Things Mean a Lot" in her honor.

In February 1976 Hollywood recognized Douglas' contribution to television, honoring him with a star on the Hollywood Walk of Fame located on Hollywood Boulevard.

In July 1978, the talk show's home base was transferred to Los Angeles, where it remained until finally going off the air in 1981. Near the end of its run, the series switched to a traveling roadshow format and became The Mike Douglas Entertainment Hour, but this change failed to boost falling ratings. After his series was cancelled, Douglas hosted CNN's Los Angeles-based Celebrity interview show, People Now, taking over the hosting duties from Lee Leonard. He was replaced in January 1983 by WTBS personality Bill Tush.

The Broadcast Pioneers of Philadelphia posthumously inducted Douglas into their Hall of Fame in 2006.